Parkinson's disease (PD) is the most common form of parkinsonism, a neurodegenerative movement disorder characterized by resting tremors, rigidity, postural instability, impaired speech and bradykinesia (slowed movement). In addition to PD, parkinsonism is exhibited in a range of conditions such as progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, and dementia with Lewy bodies. PD was first formally described in 1817 by James Parkinson in his monograph titled, “An Essay on the Shaking Palsy” (Parkinson, J.; J. Neuropsychiatry Clin. Neurosci. 2002, 14(2), 223-236 (reprinted)). He noted that the symptoms of this particular disorder include involuntary tremors, decreased muscular strength, bent posture, and difficulty walking. The pathological correlate is the loss of dopaminergic neurons in the substantia nigra of the basal ganglia and the presence of Lewy bodies (LB) in postmortem brain tissues. Aggregated α-synuclein forms the intracellular LB deposits, which are the pathological hallmark of PD and other Lewy body diseases (see e.g., Spillantini et al., Nature 1997, 388:839-840; Takeda et al., J. Pathol. 1998, 152:367-372; and Wakabayashi et al., Neurosci. Lett. 1997, 239:45-48). Most cases of PD appear not to have a genetic component. For that reason the most common form of PD is known as sporadic Parkinson's disease or idiopathic Parkinson's disease (IPD). Other forms of PD include autosomal recessive juvenile parkinsonism (AR-JP) and several rare familial forms. PD affects approximately 1-2% of the population over age 50 (˜1.5 million in the US, over 5 million worldwide) and early onset cases can occur as early as 30 (Thomas, B.; Beal, M. F.; Human Molecular Genetics 2007, 16, Review Issue 2, R183).
Current therapeutic strategies for PD focus primarily on reducing the severity of symptoms by using supplement dopaminergic medications. These drugs may lose efficacy after prolonged treatment and display severe side effects. Levodopa, a precursor of dopamine, is the most commonly prescribed drug for treatment. At present, there is no disease-modifying therapy that addresses the underlying neuropathological cause of the disease, thus constituting a significant unmet medical need. Cumulative evidence over the past decade demonstrate that autosomal mutations of several genes might be responsible for a sizable disease sub-population. A prime example is the recent discovery that dominant point mutations in Leucine-rich repeat kinase 2 (LRRK2) cause late-onset PD with clinical and pathological features indistinguishable from idiopathic PD. The extensive genetic analyses undertaken so far indicate that LRRK2 mutations are relatively frequent, accounting for 5-10% of PD cases with a positive family history (familial PD) and 1-2% of sporadic PD cases.
Leucine-rich repeat kinase 2 (also known as dardarin) is a product of the PARK8 gene. It is a member of the tyrosine kinase-like branch of the kinome. LRRK2 encodes a large multi-domain protein that consists of N-terminal leucine-rich repeats (LRR), a ROC (Ras-GTPase in complex proteins) domain, a COR (C-terminal of ROC) domain, a protein kinase domain most homologous to the RIP (Receptor Interacting Protein) kinases, and a C-terminal WD40 domain. It is expressed throughout the brain including regions associated with motor neuron dysfunction. It is also found in various other tissues, most notably in the kidneys, where expression is highest (Biskup, S.; Moore, D. J.; Rea, A.; et al. BMC Neurosci. 2007, 8:102). Levels in kidney are reported to be ˜6-fold higher than in brain (Tong, Y.; Yamaguchi, H.; Giaime, E.; et al. Proc. Natl. Acad. Sci. 2010, 107(21), 9879). Mutations in the PARK8 gene have been associated with familial PD (Paisan-Ruiz, C.; Jain, S.; Evans, E. W.; et al. Neuron, 2004, 44(4), 595). All the pathogenic mutations can lead to a wide spectrum of cellular toxicity in a kinase-dependent manner. The most prevalent amino acid substitution found in mutant LRRK2 is G2019S, which is located within the highly conserved DF/YG motif in the activation loop and causes significant increase in kinase activity.
Patients with LRRK2 mutations exhibit Lewy body pathology (Zimprich, A.; Biskup, S.; Leitner, P.; et al. Neuron, 2004, 44(4), 601), and LRRK2 is considered one of the most relevant targets for treating PD and other LB diseases. The G2019S mutation is believed to be responsible for 3-40% of familial and sporadic PD cases, dependent on study population, with Lewy body pathology most often associated with G2019S (Ross, O. A.; Toft, M.; Whittle, A. J.; et al. Ann. Neurol. 2006, 59(2), 388). Because the LRRK2 G2019S mutation has increased kinase activity, inhibition of this activity is a therapeutic target for the treatment of PD (West, A. B.; Moore, D. J.; Biskup, S.; et al. Proc. Natl. Acad. Sci. 2005, 102(46), 16842). Importantly, most of the LRRK2-mediated toxicity and pathology can be prevented by treatment with specific kinase inhibitors, suggesting that kinase inhibitors could be useful therapeutic agents for PD patients with LRRK2 mutations and potentially for sporadic PD as well. Additional LRRK2 mutations, such as 12020T, also in the kinase domain, R1441C and R1441G in the Roc domain, and Y1699C in the COR domain are also associated with PD, and mutations G2385R and R1628P are considered risk factors for sporadic PD in Asian populations (Melrose; Future Neurol. 2008, 3(6), 669-681). Animal models expressing mutant LRRK2 recapitulate certain cardinal features of human PD.
Although the function of LRRK2 is not well known at this time, the recent demonstration that LRRK2 modulates synuclein-mediated toxicity and neurodegeneration in vitro and in vivo further highlights an important role of LRRK2 in PD pathogenesis. For example, transgenic studies in mice have shown that LRRK2 may regulate α-synuclein toxicity by modulating the accumulation of α-synuclein (Lin, X.; Parisiadou, L.; Gu, X-L.; et al. Neuron 2009, 64, 807). It has also been suggested that α-synuclein neurodegeneration is related to LRRK2 regulation of cytoskeletal dynamics (Parisiadou, Loukia and Cai, Huaibin; Communicative & Integrative Biology 2010, 3(5):396-400).
Thus with involvement of LRRK2 in relation to α-synuclein toxicity, and the prevalence of LRRK2 mutant G2019S in familial PD, LRRK2 inhibitors are useful in treating PD, as well as other LBDs, such as Diffuse Lewy body disease, Lewy body variant of Alzheimner's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, and Dementia with Lewy bodies. Such inhibitors of LRRK2 for the treatment of PD and other LBDs are not well known.
Targeting of LRRK2 kinase may also provide therapeutic benefits in certain cancers, such as melanoma, acute myelogenous leukemia, breast carcinoma, lung adenocarincoma, prostate adenocarcinoma, renal cell carcinoma (e.g. papillary renal cell carcinoma), and papillary thyroid carcinoma (Looyenga et al., PNAS 2011, 108(4):1439-1444; Saunders-Pullman et al., Movement Disorders 2010, 25(15):2536-2541; and Pan et al., Internation Journal of Cancer 2011, 128(10):2251-2260), in certain autoimmune diseases, such as Inflammatory Bowel Disease (e.g. Crohn's disease and ulcerative colitis) (Gardet et al., The Journal of Immunology 2010, 185(9):5577-5585), and in leprosy (Zhang et al., The New England Journal of Medicine 2009, 361(27): 2609-2618).
There are known kinase inhibitors, in particular cFms, or PLK1 inhibitors, that are cinnoline based (U.S. Pat. No. 7,723,337, PCT publication WO 2006/124996). Other compounds have been identified as LRRK2 inhibitors, including those described in PCT publication WO 2012/062783, WO/2011/038572, WO 2010/106333, WO 2010/085799, WO 2009/127642, and WO 2009/030270 and in Deng et al., Nature Chemical Biology 2011, 7:203-205. As there are presently limited therapeutic options, there remains a need for developing potent, selective and brain-penetrant LRRK2 inhibitors for use in the treatment and/or prevention of neurodegenerative diseases or other disorders associated with LRRK2.